Liver fibrosis is a common healing response to chronic liver injury of all causes. In order to heal injured tissues, liver tissue deposits new collagen in the wound, but over time, such a process leads to liver cirrhosis. Liver fibrosis is usually associated with chronic liver diseases caused by infections, drugs, metabolic disorders, or autoimmune imbalances. Liver fibrosis caused by the parenchymal cell death and necrosis over a long period of time is associated with inflammatory response, which invites immune cells, activates and accumulates fibrogenic cells, and induces extracellular matrix accumulation. Progression of fibrosis due to continuous liver injury is associated with the expansion of the fibrotic septa and ultimately causes liver cirrhosis.
Liver fibrosis can develop into liver cirrhosis between 1 and 10 years and increases a 7- to 10-year liver-related mortality causes from 12% to 25% (Farrell, G. C. & Larter, C. Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43, S99-S112 (2006)). Unfortunately, however, effective clinical therapies are still lacking. Therefore, effective anti-fibrosis therapies are good targets for the treatment of liver diseases. Currently, anti-fibrosis strategies targeting various stages leading to liver fibrosis have been recognized. That is, there are methods of inhibiting the apoptosis of liver cells, or inhibiting liver inflammation, or promoting the apoptosis of fibrogenic cells, or returning phenotype fibrogenic cells to a quiescent state. However, specific drugs used to treat liver fibrosis so far are still limited.
Meanwhile, autophagy is a process by which eukaryotic cells digest their own cellular organs and long lived proteins as a kind of metabolic process. The process is closely associated with cell growth, differentiation and homeostasis. Further, the process is the only way to digest “long lived” or “broken” cell organs (Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721 (2000), Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Developmental cell 6, 463-477 (2004)). Autophagy acts as an important regulator of liver homeostasis under physiological and pathological conditions (Codogno, P. & Meijer, A. J. Autophagy in the liver. Journal of hepatology 59, 389-391 (2013). Rautou, P.-E. et al. Autophagy in liver diseases. Journal of hepatology 53, 1123-1134 (2010). Czaja, M. J. et al. Functions of autophagy in normal and diseased liver. Autophagy 9, 1131-1158 (2013)). Currently, autophagy has been recognized as an important pathway for regulating the supply of substrate required for homeostasis and energy production by selectively targeting specific components in cells such as aggregated protein, damaged/excess organelles, and lipids and then degrading them through lysosomal pathway (Autophagy. 2013 August; 9(8); 1131-58). Recent studies have also shown that autophagy is one new regulatory pathway related to liver fibrosis. Autophagy directly contributes to the activation process of hepatic stellate cells (HSCs) inducing hepatic fibrosis, or possibly promotes liver fibrosis by indirect action on other fibrogenic cells.
The liver, which is also a representative model of autophagy research, is characterized by: 1) very excellent reproducibility; 2) an important metabolic organ; and 3) an organ that is exposed to infection by liver trophic virus. Therefore, the core functions of the organ such as regeneration, metabolism, and immunity are closely related to autophagy (Autophagy. 2013 August; 9 (8): 1131-58). Liver ischemia-reperfusion occurs clinically during liver transplantation, trauma, shock, and elective liver resection.
During ischemia-reoxygenation, ROS (reactive oxygen species) and Ca2+ levels increase inside mitochondria, which causes mitochondria permeability transition, and oxidative phosphorylation is uncoupled, ultimately inducing apoptosis along with depletion of energy and ATP. Because autophagy proteins are inhibited during anoxia/reoxygenation, the damaged mitochondria are not removed. Therefore, a strategy to activate tolerance to ischemia-reperfusion by activating autophagy has been attempted in preclinical models. Meanwhile, in the acute liver injury model, autophagy is activated to increase cell survival in stress situations.
PI3K/AKT/mTOR signaling pathway regulates various cellular processes such as cell growth or proliferation, motility, survival, apoptosis, protein synthesis and transcription (Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes & development 18, 1926-1945 (2004). Yang, Q. & Guan, K.-L. Expanding mTOR signaling. Cell research 17, 666-681 (2007). Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253-262 (2000). Sarbassov, d. D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. Current opinion in cell biology 17, 596-603 (2005)). Further, the PI3K/AKT/mTOR signaling pathway is well known as a major pathway in autophagy. If mTOR signaling is inhibited due to lack of nutrition and growth factors, autophagy is induced. On the contrary, when nutrition and growth factors are abundant, mTORC1 is activated, thereby inhibiting autophagy through ULK1 complex and promoting cell growth and metabolic activity. Many experimental data reported that the AKT/mTOR signaling pathway is at the center of HSCs activation (Reif, S. et al. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-akt signaling in hepatic stellate cell proliferation and type I collagen expression. Journal of Biological Chemistry 278, 8083-8090 (2003). Gabele, E. et al. The role of p70S6K in hepatic stellate cell collagen gene expression and cell proliferation. Journal of Biological Chemistry 280, 13374-13382 (2005). Gabele, E., Brenner, D. A. & Rippe, R. A. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosci 8, 69-d77 (2003)). Inhibition of mTOR signaling pathway by mTOR inhibitor Rapamycin has been reported to reduce fibrous tissue growth, improve liver function and reduce portal pressure in animal models of liver cirrhosis (Biecker, E. et al. Long-term treatment of bile duct-ligated rats with rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms. Journal of Pharmacology and Experimental Therapeutics 313, 952-961 (2005). Neef, M., Ledermann, M., Saegesser, H., Schneider, V. & Reichen, J. Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. Journal of hepatology 45, 786-796 (2006). Patsenker, E. et al. Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis. Journal of hepatology 55, 388-398 (2011)). In addition, Rapamycin is used as a primary immunosuppressive agent in liver transplant patients, and Sirolimus and Everolimus, which are mTOR inhibitors, have been reported to reduce fibrosis progression and portal hypertension under experimental conditions.
Therefore, the present inventors have learned from the above-mentioned prior studies that autophagy plays a crucial role in liver diseases, and based on the findings, the inventors have conducted intensive studies to develop a compound that can induce activity of autophagy. As a result, the inventors have found that novel catechol derivatives as described below have excellent effects for activating autophagy and activities for inhibiting liver diseases, thereby completing the present invention.